DESCRIPTION: (Applicant's Description) Advanced, hormone-refractory prostate cancer (HRPC) is inevitably fatal (median survival approximately one year), and no post-hormonal therapy regimen has been demonstrated to extend survival. The primary objective and first specific aim (SA) of this proposal is to determine if the investigational agent arsenic trioxide (ATO), which ha not previously been tested in prostate cancer, has significant clinical activity in HRPC with documented metastases (D1-D2 disease) as tested in a two-stage phase II trial design with early termination for insufficient agent efficacy. Other clinical objectives of the phase II trial are to assess the toxicity of ATO in an elderly patient population (SA2) and to preliminarily assess the effect of ATO on pain control in HRPC (SA3). The scientific bases for the trial regimen (a moderately-high dose of ATO, 0.2 rog/kg/day, administered over substantial time prior to definitive response evaluation, 10 of the first 14 days on a 28-day cycle x 4 cycles) are: (a) that ATO has approximately equal acute cytotoxic activity in androgen-independent prostate cancer cultured cells (LNCaP/AI) as in parental androgen-dependent cells (LNCaP/AD), in contrast to the markedly reduced activity of other agents on the AI cells and (b) that the pattern of ATO activity in the LNCaP system with dose-dependent acute and chronic anti-tumor cell activity significantly parallels that in acute promyelocytic leukemia in which it is highly active in drug-resistant disease. There are three associated laboratory objectives. SA 4 is to assess the value of measuring changes in circulating prostate cancer cell levels using a highly sensitive and quantitative reverse-transcriptase-polymerase chain reaction (RT-PCR) method (real-time RT-PCR) to monitor levels of taRNAs encoding prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSIvi) in the peripheral blood. This SA is formulated both from concern that the phase II protocol-specified response measures, changes in measurable disease (evaluable in approximately 10 percent of cases) or the surrogate marker serum PSA, may not be optimal for monitoring ATO activity and from the investigators' experience with real-time RT-PCR monitoring. SA 5 is to perform pharmacokinetic and pharmacodynamic analyses of ATO in the novel phase II setting. SA 6 is to preliminarily assess whether two measurements of metastatic prostate cancer cells in pretreatment bone marrow have outcome predictive value: (a) the PSA:PSM mRNA expression ratio, which may vary with HRPC phenotypic properties affecting response and (b) the absence/presence of pi-class glutathione S-transferase, which may influence the activity of ATO in HRPC.